PROJECT SUMMARY/ABSTRACT In healthy adult humans the lymphatic vasculature collects as much as 12 liters of lymph per day. Defects in lymphatic vascular function lead to lymphedema, which is characterized by the swelling of limbs. Additional health problems caused by lymphedema include fibrosis, hypertension, obesity and even cancer. While palliative treatments are available, they are never curative. Barriers to advancing new therapies include a remarkably limited present understanding of lymphatic functional anatomy and genetic controls. Lymph collected by lymphatic vessels is transported through collecting lymphatic vessels in which lymphatic valves prevent fluid stasis. Finally, lymph is returned to the blood circulation via four lymphovenous valves. Defects in lymphatic or lymphovenous valves are associated with lymphedema. The objective of this application is to better define the mechanisms of valve development, which remain poorly understood and is a critical barrier for treating lymphedema. We have determined that Wnt/?-catenin signaling pathway is necessary for the development of lymphatic and lymphovenous valves. Building on key preliminary data we will attempt to identify the upstream activators and downstream targets of Wnt/?-catenin signaling pathway. Numerous agonists and antagonists of Wnt/?-catenin signaling pathway are available. Therefore, our findings could translate into innovative approaches to treat human lymphedema patients.